CN107233629A - Injection aquagel and its preparation and application - Google Patents
Injection aquagel and its preparation and application Download PDFInfo
- Publication number
- CN107233629A CN107233629A CN201710473363.0A CN201710473363A CN107233629A CN 107233629 A CN107233629 A CN 107233629A CN 201710473363 A CN201710473363 A CN 201710473363A CN 107233629 A CN107233629 A CN 107233629A
- Authority
- CN
- China
- Prior art keywords
- raw material
- injection aquagel
- butyraldehyde
- hydrogel
- polyethylene glycol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002347 injection Methods 0.000 title claims abstract description 56
- 239000007924 injection Substances 0.000 title claims abstract description 56
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 57
- 239000000017 hydrogel Substances 0.000 claims abstract description 45
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 21
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 19
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 19
- 239000000463 material Substances 0.000 claims abstract description 15
- 239000003292 glue Substances 0.000 claims abstract description 12
- 239000003937 drug carrier Substances 0.000 claims abstract description 7
- 208000005189 Embolism Diseases 0.000 claims abstract description 4
- -1 butyraldehyde-polyethylene Chemical group 0.000 claims description 22
- 239000007853 buffer solution Substances 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 12
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 claims description 6
- 239000000872 buffer Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 230000004048 modification Effects 0.000 claims description 5
- 238000012986 modification Methods 0.000 claims description 5
- 229960002319 barbital Drugs 0.000 claims description 3
- GHXRKGHKMRZBJH-UHFFFAOYSA-N boric acid Chemical compound OB(O)O.OB(O)O GHXRKGHKMRZBJH-UHFFFAOYSA-N 0.000 claims description 3
- PMUNIMVZCACZBB-UHFFFAOYSA-N 2-hydroxyethylazanium;chloride Chemical compound Cl.NCCO PMUNIMVZCACZBB-UHFFFAOYSA-N 0.000 claims description 2
- SWSHKRHJENMKJJ-UHFFFAOYSA-L O.[Na+].P(=O)(O)(O)[O-].[K+].P(=O)(O)(O)[O-] Chemical compound O.[Na+].P(=O)(O)(O)[O-].[K+].P(=O)(O)(O)[O-] SWSHKRHJENMKJJ-UHFFFAOYSA-L 0.000 claims description 2
- 239000008367 deionised water Substances 0.000 claims description 2
- 229910021641 deionized water Inorganic materials 0.000 claims description 2
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 claims description 2
- 238000011068 loading method Methods 0.000 claims description 2
- 239000007981 phosphate-citrate buffer Substances 0.000 claims description 2
- 229940126586 small molecule drug Drugs 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Substances [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 2
- OTNVGWMVOULBFZ-UHFFFAOYSA-N sodium;hydrochloride Chemical compound [Na].Cl OTNVGWMVOULBFZ-UHFFFAOYSA-N 0.000 claims description 2
- LEAHFJQFYSDGGP-UHFFFAOYSA-K trisodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].OP(O)([O-])=O.OP([O-])([O-])=O LEAHFJQFYSDGGP-UHFFFAOYSA-K 0.000 claims description 2
- 239000004698 Polyethylene Substances 0.000 claims 1
- 230000003139 buffering effect Effects 0.000 claims 1
- 239000011545 carbonate/bicarbonate buffer Substances 0.000 claims 1
- CIJQGPVMMRXSQW-UHFFFAOYSA-M sodium;2-aminoacetic acid;hydroxide Chemical compound O.[Na+].NCC([O-])=O CIJQGPVMMRXSQW-UHFFFAOYSA-M 0.000 claims 1
- POECFFCNUXZPJT-UHFFFAOYSA-M sodium;carbonic acid;hydrogen carbonate Chemical compound [Na+].OC(O)=O.OC([O-])=O POECFFCNUXZPJT-UHFFFAOYSA-M 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 150000002466 imines Chemical class 0.000 abstract description 9
- 230000008901 benefit Effects 0.000 abstract description 6
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 abstract 8
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 abstract 4
- 239000003814 drug Substances 0.000 description 36
- 239000000499 gel Substances 0.000 description 25
- 229940079593 drug Drugs 0.000 description 20
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 16
- 206010010254 Concussion Diseases 0.000 description 10
- 230000009514 concussion Effects 0.000 description 10
- 238000009825 accumulation Methods 0.000 description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- 229940009456 adriamycin Drugs 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 238000001879 gelation Methods 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 238000011065 in-situ storage Methods 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108010015776 Glucose oxidase Proteins 0.000 description 3
- 239000004366 Glucose oxidase Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229940116332 glucose oxidase Drugs 0.000 description 3
- 235000019420 glucose oxidase Nutrition 0.000 description 3
- 239000003999 initiator Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- 101710186708 Agglutinin Proteins 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- 101710146024 Horcolin Proteins 0.000 description 2
- 101710189395 Lectin Proteins 0.000 description 2
- 101710179758 Mannose-specific lectin Proteins 0.000 description 2
- 101710150763 Mannose-specific lectin 1 Proteins 0.000 description 2
- 101710150745 Mannose-specific lectin 2 Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000000910 agglutinin Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000010382 chemical cross-linking Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000007979 citrate buffer Substances 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 2
- 229940081974 saccharin Drugs 0.000 description 2
- 235000019204 saccharin Nutrition 0.000 description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 229920000463 Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) Polymers 0.000 description 1
- 241000219000 Populus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- LXDRHVXMGDKBEK-UHFFFAOYSA-N [B].C1=CC=CC=C1 Chemical compound [B].C1=CC=CC=C1 LXDRHVXMGDKBEK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- HDFXRQJQZBPDLF-UHFFFAOYSA-L disodium hydrogen carbonate Chemical compound [Na+].[Na+].OC([O-])=O.OC([O-])=O HDFXRQJQZBPDLF-UHFFFAOYSA-L 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000007986 glycine-NaOH buffer Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000010526 radical polymerization reaction Methods 0.000 description 1
- 238000013102 re-test Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000000518 rheometry Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/26—Mixtures of macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/041—Mixtures of macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/145—Hydrogels or hydrocolloids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Surgery (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Vascular Medicine (AREA)
- Dispersion Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of injection aquagel and its preparation and application.The injection aquagel is constituted by raw material A, raw material B and into glue；The mass percent of raw material A and raw material B quality sum in hydrogel is 5% 50%, and wherein raw material A is butyraldehyde polyethylene glycol butyraldehyde, and raw material B is the polyethylene glycol that four arm Amino End Groups are modified；The amino of the main polyethylene glycol modified using four arm Amino End Groups and the imines dynamic key of the aldehyde radical formation of butyraldehyde polyethylene glycol butyraldehyde obtain syringeability hydrogel；The injection aquagel can be applied as pharmaceutical carrier, embolism materials or tissue engineering material etc..The preparation method of the injection aquagel, including step：Raw material A and raw material B addition glues are well mixed, injection aquagel is obtained；It is easy, quick with preparation process, it is easy to the advantage of large-scale production.
Description
Technical field
The invention belongs to biomolecule pharmaceutical technology field, and in particular to a kind of injection aquagel and its preparation and should
With.
Background technology
Hydrogel is the three-dimensional net structure by high molecular crosslink, in biomedicine field such as insoluble drug release, organizational project
Had a wide range of applications with bio-sensing etc..In minimally invasive medical and injectable organizational project, Injectable in-situ gel system by
Extensive concern is arrived.Gel-in-matrix before the injection by biomolecule or mixing with cells in the solution, through injection can will bear
The timbering material for having carried biomolecule or cell is implanted to and needs position, after gelation, becomes and is released for the medicine in pharmaceutical preparation
Put basic point or the cell growth basic point of regeneration, it is to avoid operation implantation it is painful and cumbersome, and cells in situ fixation also has
Beneficial to one irregular tissue defects of filling.
At present, preparing the method for situ-gel system has chemical crosslinking and is physical crosslinking, and chemical crosslinking includes radical polymerization
Conjunction and Michael's addition etc., it usually needs add initiator or generation small molecule by-product, physical crosslinking passes through physical change bag
Include the change realization such as pH value, temperature and ionic strength.The hydrogel (i.e. dynamic key gel) constructed using dynamic covalent bond is had
Higher mechanical strength and syringeability, and because sensitive group is chemical bond, so as to greatly widen optional macromolecule material
The scope of material, can construct the hydrogel with multiple response.Poplar etc. can construct pH/ temperature sensitives using saccharin key
Injectable chitosan matrix hydrogel, saccharin key has physiological pH response, can trigger gel by adjusting pH value
Formation and destruction, it is not necessary to initiator, and the small molecule product of the reaction is water, it is to avoid impurity draws in gel process
Enter；The hydrogel of formation has preferable mechanical strength, and at macromolecule content relatively low (5.0wt%), its modulus of elasticity is reachable
103-104Pa, the hydrogel can be used for the long-acting controlled release of antineoplastic, and achieve preferable oncotherapy effect
(Dually Responsive Injectable Hydrogel Prepared by In Situ Cross-Linking of
Glycol Chitosan and Benzaldehyde-Capped PEO-PPO-PEO,Biomacromolecules 2010,
11,1043-1051).Borate ester is reacted by phenyl boronic acid derivative and polyol to be formed, and reaction does not need initiator,
Do not produce other accessory substances than water, with glucose oxidase (GOx), agglutinin be construct glucose responding system three
Big system.Glucose oxidase and agglutinin are protein compound, and harsher to environmental requirement, the change of external environment can
It can be caused to inactivate, limit its application.And the diversity and more preferable stability that imine linkage is designed due to it, in development Portugal
There is larger advantage in terms of grape sugar Response System, cause researchers and more widely pay close attention to.There is document report by benzene boron
Gel and microgel that acid and NIPA (PNIPAM) are constituted, can be swelled and release in the presence of glucose
Release insulin, but these materials ability only under higher than phenyl boric acid pKa value (pH 9) and higher concentration of glucose (20g/L)
With glucose responding, the application of its (pH 7.4, concentration of glucose 1-3g/L) in physiological conditions is limited
(Synthesis and Volume Phase Transitions of Glucose-Sensitive Microgels,
Biomacromolecules 2006,7,3196-3201,Phenylboronic acid-based glucose-
responsive polymeric nanoparticles:synthesis and applications in drug
delivery,Polym.Chem.,2014,5,1503-1518)。
The content of the invention
In order to overcome the deficiencies in the prior art, the invention provides a kind of biodegradable injectable water-setting of safety non-toxic
Glue, the aldehyde radical shape of the amino and butyraldehyde-polyethylene glycol-butyraldehyde of the main polyethylene glycol using the modification of the arm Amino End Group of specific structure four
Into imines dynamic key obtain syringeability hydrogel.
It is easy, quick with preparation process, it is easy to big present invention also offers the preparation method of the injection aquagel
The advantage of large-scale production.
The concrete technical scheme that the present invention takes is as follows：
A kind of injection aquagel, is constituted by raw material A, raw material B and into glue；The quality sum of the raw material A and raw material B
Mass percent in hydrogel is 5%-50%, and wherein raw material A is butyraldehyde-polyethylene glycol-butyraldehyde, and raw material B is four arm ends
Amido modified polyethylene glycol；
The structural formula of the butyraldehyde-polyethylene glycol-butyraldehyde is as shown in formula I：
M is 10-16000 integer in formula I, formula I；
The structural formula of the polyethylene glycol of the four arms Amino End Group modification is as shown in formula II：
N is in formula II, formula II
565-5700 integer.
Injection aquagel of the present invention, using four arm Amino End Groups shown in butyraldehyde-polyethylene glycol-butyraldehyde shown in formula I and formula II
The polyethylene glycol of modification, both structures are the macromolecular with good aqueous solubility, the polyethylene glycol of four arm Amino End Groups modification
In four arm configurations the network with hydrophilic soft segment, butyraldehyde-polyethylene glycol-butyraldehyde can be provided for hydrogel
Linear chain structure also act as soft segment, both distinctive structures ensure that the hydrogel to be formed has in aqueous
Porous and fine and close structure, obtained hydrogel has excellent flexibility and elasticity, and slow release effect is controllable；Meanwhile, four arm ends
The amino of amido modified polyethylene glycol and the imines dynamic key of the aldehyde radical formation of butyraldehyde-polyethylene glycol-butyraldehyde have to pH rings
Ying Xing, can be formed in situ the gel that uniform state is presented, can be implanted by injection system.
Consider raw material A and the specific chemical constitutions of raw material B, in order to reach more preferable invention effect, preferably：
The raw material A and raw material B mass ratio are (0.5-25)：1, the stability and injectable of hydrogel can be strengthened
Property.
The mass percent of the raw material A and raw material B quality sum in hydrogel is 5%-30%, further preferably
For 5%-20%, most preferably 5%-15%.When raw material A and raw material B gross mass percentage concentration is 5%-20%, injectivity is more
It is excellent；When raw material A and raw material B gross mass percentage concentration are more than 20% and are less than or equal to 50%, the stability of gel is more preferable.It is former
When the gross mass percentage concentration for expecting A and raw material B is 5%-15%, not only injectivity is excellent, and preferably in human normal body
Quick-gelatinizing under the conditions of warm scope (general 36.0 DEG C -37.5 DEG C) and normal physiological pH7.4.The present invention can be according to hydrogel
Application field is different, selects suitable raw material A and raw material B gross mass concentration range.
It is described to select deionized water or pH value in 6-8 cushioning liquid into glue, provide plastic environment for hydrogel.
The cushioning liquid can using disodium hydrogen phosphate-citrate buffer solution, potassium dihydrogen phosphate-sodium hydrate buffer solution,
Disodium hydrogen phosphate-phosphate sodium dihydrogen buffer solution, barbital sodium-hydrochloride buffer, three (methylol) aminomethane-hydrochloride buffers
(Tris-HCl buffer solutions), boric acid-borate buffer solution, Glycine-NaOH buffer solution, borax-sodium hydrate buffer solution, carbon
One or more in the cushioning liquid such as sour sodium-sodium bicarbonate buffer liquid.
According to the requirement of its application field, it is described can select into glue it is sterile into glue.
The preparation method of the injection aquagel, including step：
Raw material A and raw material B addition glues are well mixed, injection aquagel is obtained.
The formation temperature of the injection aquagel is at 20 DEG C -38 DEG C.
Raw material used in the present invention can be prepared using commercially available prod or using existing preparation method.
The injection aquagel, with pH responses and syringeability, can be used as pharmaceutical carrier, embolism materials or group
Knit the application such as engineering material.The injection aquagel uses the raw material A and raw material B of specific structure and molecular weight ranges, especially
Beneficial to the pharmaceutical carrier as load small-molecule drug such as adriamycin (DOX), drug release rate can adjust.
The invention has the advantages that：
(1) raw material of subject hydrogel uses the macromolecular with good aqueous solubility, and raw material safety non-toxic itself can give birth to
Thing is degraded, and the forming process of gel overcomes potential safety hazard when being used in water gel without using organic solvent.Raw material A
It is existing high-molecular compound with raw material B, it is chemical synthesis that it, which is originated, compared to coming from that current hydrogel is largely used
High-molecular compound in plant and animal body, the raw material of chemical synthesis has structure-controllable system, it is easier to adjust hydrogel
The advantages such as intensity, degradation speed, drug releasing rate.
(2) subject hydrogel is mainly the aldehyde on the amino in specific structure macromolecular and another specific structure macromolecular
Base reacts to form imine linkage, more stable under normal body temperature's scope and normal physiological pH value, can be by under solutions of weak acidity
Gradually hydrolyze to form solution.Because imine linkage is relatively stablized under normal physiological conditions, easily hydrolyze under mildly acidic conditions, this hair
It is bright can by adjust two kinds of raw materials ratio, control generation imine linkage ratio so that intelligence control gel formation when
Between, the degradation rate of the release of the compactness extent of gel, medicine and gel.
(3) subject hydrogel has certain intensity and toughness, due to generating imine linkage during gel is formed,
With self-repairability, gelling performance can be regulated and controled by the molecular weight of raw material and the ratio of raw material, further increase the life of gel
Thing compatibility；Gel prepared by the present invention has biodegradability, can be by body metabolism；With pH responses and injectable
Property, it can be used as pharmaceutical carrier, embolism materials and tissue engineering material etc..
(4) preparation method of injection aquagel of the present invention is easy, quick with preparation process, it is easy to mass produce
Advantage.
Brief description of the drawings
Fig. 1 is the electron-microscope scanning figure of injection aquagel in the embodiment of the present invention 1；
Fig. 2 is the rheogram of injection aquagel in the embodiment of the present invention 3；Wherein G ' expressions storage modulus, G " represent to damage
Consume modulus；
Fig. 3 is bent for the drug accumulation release under medicine injection aquagel is carried in application examples 3 of the present invention in two kinds of pH environment
Line chart；
Fig. 4 is the medicine cumulative release curve in pH7.4 environment of load medicine injection aquagel in application examples 1 of the present invention
Figure.
Embodiment
With reference to specific embodiment to further description of the present invention.Present embodiment is not to its protection domain
Limitation.
Embodiment 1
0.5g butyraldehyde-polyethylene glycol-butyraldehyde (m=100) and the arm Amino End Groups of 1g tetra- are modified polyethylene glycol (n=1000,
Laysan) plus 28.5g aseptic deionized waters, 37 DEG C of rapid concussions are well mixed, obtain that 30g is transparent, uniform state after 35 seconds
Injection aquagel.
The electron-microscope scanning figure of the injection aquagel is shown in Fig. 1, and display hydrogel has porous and fine and close structure, and aperture exists
0.1mm-0.4mm。
Embodiment 2
5g butyraldehyde-polyethylene glycol-butyraldehyde (m=16000) and the arm Amino End Groups of 1g tetra- are modified polyethylene glycol (n=5000,
Laysan 34g disodium hydrogen phosphates-citrate buffer solution (pH=6.5)) is added, 37 DEG C of rapid concussions are well mixed, obtained after 30 seconds
40g is transparent, uniform state injection aquagel.
The electron-microscope scanning figure of gained injection aquagel shows that hydrogel has porous and fine and close structure, and aperture exists
0.1mm-0.3mm。
Embodiment 3
Polyethylene glycol (the n=that 14g butyraldehyde-polyethylene glycol-butyraldehyde (m=10000) and the arm Amino End Groups of 1g tetra- are modified
5700, Laysan) 85g disodium hydrogen phosphates-phosphate sodium dihydrogen buffer solution (pH=7.4) is added, 37 DEG C of rapid concussions are well mixed, 25
Obtain that 100g is transparent, uniform state injection aquagel after second.
The electron-microscope scanning figure of gained injection aquagel shows that hydrogel has porous and fine and close structure, and aperture exists
0.1mm-0.3mm。
Embodiment 4
25g butyraldehyde-polyethylene glycol-butyraldehyde (m=10) and the arm Amino End Groups of 1g tetra- are modified polyethylene glycol (n=565,
Laysan 234g barbital sodiums-hydrochloride buffer (pH=6)) is added, 38 DEG C of rapid concussions are well mixed, and obtaining 260g after 32 seconds is in
Transparent, uniform state injection aquagel.
The electron-microscope scanning figure of gained injection aquagel shows that hydrogel has porous and fine and close structure, and aperture exists
0.1mm-0.3mm。
Embodiment 5
20g butyraldehyde-polyethylene glycol-butyraldehyde (m=5000) and the arm Amino End Groups of 1g tetra- are modified polyethylene glycol (n=2500,
Laysan 84g Tris-HCl buffer solutions (pH=6.4)) are added, 37 DEG C of rapid concussions are well mixed, and 105g is obtained after 22 seconds in thoroughly
Bright, uniform state injection aquagel.
The electron-microscope scanning figure of gained injection aquagel shows that hydrogel has porous and fine and close structure, and aperture exists
0.1mm-0.2mm。
Embodiment 6
25g butyraldehyde-polyethylene glycol-butyraldehyde (m=8000) and the arm Amino End Groups of 1g tetra- are modified polyethylene glycol (n=4000,
Laysan 61g Glycine-NaOHs buffer solution (pH=7.6)) is added, 20 DEG C of rapid concussions are well mixed, and 87g is obtained after 18 seconds
Transparent, uniform state injection aquagel.
The electron-microscope scanning figure of gained injection aquagel shows that hydrogel has porous and fine and close structure, and aperture exists
0.1mm-0.3mm。
Embodiment 7
Polyethylene glycol (the n=that 10g butyraldehyde-polyethylene glycol-butyraldehyde (m=13000) and the arm Amino End Groups of 1g tetra- are modified
3200, Laysan) 11g boric acid-borate buffer solution (pH=8) is added, 30 DEG C of rapid concussions are well mixed, and obtaining 22g after 12 seconds is in
Transparent, uniform state injection aquagel.
The electron-microscope scanning figure of gained injection aquagel shows that hydrogel has porous and fine and close structure, and aperture exists
0.1mm-0.3mm。
The property of subject hydrogel Drug controlled release is explored using adriamycin as model drug：
Application examples 1
The poly- second that adriamycin 500mg, 0.5g butyraldehyde-polyethylene glycol-butyraldehyde (m=100) and the arm Amino End Groups of 1g tetra- are modified
Glycol (n=1000, Laysan) plus 28.4g aseptic deionized waters, 37 DEG C of rapid concussions are well mixed, and obtaining 30g after 35 seconds is in
Transparent, uniform state injectable carries liquid medicine gel, envelop rate 85%, drugloading rate 1.42%.
Application examples 2
The poly- second that adriamycin 700mg, 5g butyraldehyde-polyethylene glycol-butyraldehyde (m=16000) and the arm Amino End Groups of 1g tetra- are modified
Glycol (n=5000, Laysan) plus 33.9g disodium hydrogen phosphates-citrate buffer solution (pH=6.5), 37 DEG C of rapid concussion mixing
Uniformly, obtain that 40g is transparent, injectable of uniform state carries liquid medicine gel, envelop rate 90%, drugloading rate 1.58% after 30 seconds.
Application examples 3
By adriamycin 1.5g, 14g butyraldehyde-polyethylene glycol-butyraldehyde (m=10000) and the amido modified poly- second of the arm of 1g ends four
Glycol (n=5700, Laysan) plus 84.9g disodium hydrogen phosphates-phosphate sodium dihydrogen buffer solution (pH=7.4), 37 DEG C of rapid concussions
It is well mixed, obtain that 100g is transparent, uniform state injectable carries liquid medicine gel, envelop rate 92%, drugloading rate after 25 seconds
1.38%.
Subject hydrogel, shortens, the gelation time of hydrogel can be square with the increase gelation time of polymer concentration
Just control was at -35 seconds 12 seconds.Subject hydrogel gelation time is shorter, and each raw material and solution are avoided when can inject in the original location
Gel molecular concentration moment is diluted by body fluid etc. and influences the formation of hydrogel after mixing, with syringeability, can it is in situ into
Glue.
Injection aquagel in embodiment 1-6 is used into survey of the rheometers of RS 6000 (Thermo-Fisher) at 37 DEG C
Try to carry out rheological analysis test, by taking the rheogram (as shown in Figure 2) of injection aquagel in embodiment 3 as an example, rheology on platform
As a result show：Increasing over time storage modulus G ' and loss modulus G " gradually strengthens, same time condition storage modulus G '
Significantly greater than loss modulus G ", shows that subject hydrogel is mesh-structured for elasticity.
In application examples 1-3 after hydrogel carrying medicament, the gelation time of hydrogel does not change, and shows subject hydrogel
Gel can be quickly formed before and after carrying medicament, good syringeability is respectively provided with.
Gained in application examples 1-3 is carried into liquid medicine gel to be placed in 10ml pH=7.4 phosphate buffer solution (PBS is molten
Liquid) or pH=6.5 PBS solution in, 37 DEG C, vitro drug release is carried out in 40rpm constant temperature oscillators, when multiple
Between select (T) and take 1ml supernatants, the fresh PBS solution for filling into 1ml after supernatant in time is taken every time, using the detection of HPLC methods it is each when
Doxorubicin content in section supernatant (sample), calculates drug accumulation release rate (%).
HPLC testing conditions：Dissolved again with 0.5mL mobile phases, with RPLC (RP-HPLC, Agilent
1200, Agilent Technologies Inc., USA) detect its concentration.20 μ L samples are expelled to ZORBAX Eclipse
Plus C18 chromatographic columns (150mm × 4.6mm), 5.0 μm, Agilent Corp., USA) in, washed with 1mL/min elution speed
De-, flowing phase composition is acetonitrile/water/methanol (48/41/11, v/v/v), and ultraviolet detection wavelength is 227nm.DOX in release liquid
Content detects that Detection wavelength is 485nm with ultraviolet-visible spectrophotometer.Releasing result is with the average value of three retests
Draw.
Drug accumulation release rate=(T time insoluble drug release gross mass ÷ actual loadings drug quality) × 100%.
The drug accumulation releasing curve diagram of the load medicine injection aquagel of application examples 3 is shown under Fig. 3, different pH condition, medicine
Thing rate of release is different, shows that injection aquagel of the present invention has pH responses, when pH7.4, drug releasing rate
It is relatively slow, under mildly acidic conditions (during such as pH6.5), due to unstable, the reduction of gel cross-linkage point, drug releasing rate of imine linkage
Accelerate.
The drug accumulation releasing curve diagram of the load medicine injection aquagel of application examples 1 is shown in Fig. 4, and the load medicine of application examples 2 can be noted
The drug accumulation releasing result of jetting gel and the drug accumulation releasing result of application examples 1 are essentially identical, its drug release patterns
Shown in figure, the adriamycin in subject hydrogel can be sustained, and it can be effectively sustained up to 12 hours.
The drug accumulation releasing result that the present invention carries medicine injection aquagel shows this gel delivery systme as chemotherapy
There is application value in slow releasing carrier of medication.There is degradability additionally, due to subject hydrogel, in the material implanted, such as bolt
There is application value in plug material or tissue engineering material etc. field.
Claims (10)
1. a kind of injection aquagel, it is characterised in that the injection aquagel is constituted by raw material A, raw material B and into glue；
The mass percent of the raw material A and raw material B quality sum in hydrogel is 5%-50%, and wherein raw material A is butyraldehyde-poly-
Ethylene glycol-butyraldehyde, raw material B is the polyethylene glycol that four arm Amino End Groups are modified；
The structural formula of the butyraldehyde-polyethylene glycol-butyraldehyde is as shown in formula I：
M is 10-16000 integer in formula I；
The structural formula of the polyethylene glycol of the four arms Amino End Group modification is as shown in formula II：
N is 565-5700 integer in formula II；
It is described into glue be the cushioning liquid of deionized water or pH value in 6-8.
2. injection aquagel according to claim 1, it is characterised in that the raw material A and raw material B mass ratio is
(0.5-25)：1.
3. injection aquagel according to claim 1 or 2, it is characterised in that the raw material A and raw material B quality it
It is 5%-30% with the mass percent in hydrogel.
4. injection aquagel according to claim 1 or 2, it is characterised in that the raw material A and raw material B quality it
It is 5%-20% with the mass percent in hydrogel.
5. injection aquagel according to claim 1 or 2, it is characterised in that the raw material A and raw material B quality it
It is 5%-15% with the mass percent in hydrogel.
6. injection aquagel according to claim 1, it is characterised in that the cushioning liquid using disodium hydrogen phosphate-
Citrate buffer solution, potassium dihydrogen phosphate-sodium hydrate buffer solution, disodium hydrogen phosphate-phosphate sodium dihydrogen buffer solution, barbital sodium-
Hydrochloride buffer, three (methylol) aminomethane-hydrochloride buffers, boric acid-borate buffer solution, Glycine-NaOH buffering
One or more in liquid, borax-sodium hydrate buffer solution, sodium carbonate-bicarbonate buffer solution.
7. the preparation method of the injection aquagel according to claim any one of 1-6, it is characterised in that including step：
Raw material A and raw material B addition glues are well mixed, injection aquagel is obtained.
8. the preparation method of injection aquagel according to claim 7, it is characterised in that the injection aquagel
Temperature is formed at 20 DEG C -38 DEG C.
9. the injection aquagel according to claim any one of 1-6 is being used as pharmaceutical carrier, embolism materials or tissue
Application in engineering material.
10. application according to claim 9, it is characterised in that described pharmaceutical carrier is for loading small-molecule drug
Pharmaceutical carrier.
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